Objectives: The aim of the study was to investigate the role of 18fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for evaluating the efficacy of radiofrequency ablation (RFA) in primary and metastatic liver tumors compared with contrast-enhanced ultrasound examination (CEUS) and to find its place in overall staging and the follow-up diagnostic algorithm. Methods: PET/CT examinations were performed 2 months after RFA for 20 patients with a total of 34 liver lesions. CEUS was performed within 10 days after PET/CT, and the results were compared. Seven patients were staged with PET/CT and the others with a contrast-enhanced CT. Results: A total of 48 18F-FDG PET/CT examinations were performed. We observed complete response in 8 patients (40%), 2 patients (10%) had stable disease, one (5%) had partial response, and 9 patients (45%) had progression (including 2 cases with extrahepatic involvement). Compared with CEUS, there was a mismatch in 3 cases. Five patients underwent additional RFA for 7 lesions. Conclusion: According to our preliminary data, PET/CT may be a valuable method, with comparable or eventually even better sensitivity than CEUS, for early evaluation of the efficacy of RFA for the treatment of metastatic and primary liver lesions and planning of future treatment. PET/CT might be recommended as a staging method before undergoing RFA of liver lesions for determining the local extent of the disease in the liver in combination with CEUS with an advantage in visualization of extrahepatic involvement. However, more patients need to be investigated in order to demonstrate and confirm the obtained results with certainty.